1. FIELD OF THE INVENTION
The present invention is directed to certain selected transient pro-drug forms of conventional anti-inflammatory steroids (e.g., cortisone, hydrocortisone, prednisone, prednisolone, etc.) useful in alleviating inflammatory conditions in warm-blooded animals.
For the purposes of this application, the term "pro-drug" denotes a derivative of a known and proven prior art anti-inflammatory steroid compound (e.g., cortisone, hydrocortisone, prednisone, prednisolone, etc.), which derivative, when administered to a warm-blooded animal, "cleaves" in such a manner as to release the proven drug form at its target site or sites of activity.
The term "transient" denotes enzymatic and/or chemical hydrolytic "cleavage" of the compounds of the instant invention in such a manner such that the proven drug form (the conventional antiinflammatory steroid, e.g., cortisone, hydrocortisone, prednisone, prednisolone, etc.) is released while the remaining "cleaved" moiety remains nontoxic and is metabolized in such a manner that nontoxic, metabolic products are produced.
Finally, the term "pharmaceutically acceptable acid addition salt" as used herein generally includes the nontoxic acid addition salts of selected compounds of formulas (I) and (II), formed with nontoxic inorganic or organic acids. For example, the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycollic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric, sulfonic, toluenesulfonic, and the like.
2. BACKGROUND OF THE INVENTION
Conventional anti-inflammatory steroids such as cortisone, hydrocortisone, prednisone, prednisolone, etc. are large molecular weight steroidal compounds containing a number of hydrophilic functions, e.g., hydroxyl and keto functions. These compounds are characterized as having (1) extremely low water solubility, (2) extensive intermolecular hydrogen bonding due to the combination of hydrophilic functions such as --OH and .dbd.O (as evidenced by their high melting point, and (3) high molecular weight.
All three points enumerated above contribute to the inefficient and slow penetrability of these conventional steroidal compounds through biological barriers, among which the most important are (1) the skin and (2) the gastrointestinal wall.
It is recognized that in the case of the skin, the higher molecular weight anti-inflammatory steroids are absorbed primarily through the appendages and the hair follicles as opposed to the more efficient molecular interacellular absorption. See, M. Katz and B. J. Poulsen, Absorption of Drugs through the Skin, Handbook of Experimental Pharmacology, Vol. XXVII/I, Chapter 7, page 104, Springer Verlag, Berlin -- Heidelberg -- New York, 1971.
In view of the foregoing, it is apparent that a need exists for a class of novel anti-inflammatory steroidal compounds which will overcome the aforementioned inefficiencies such that penetration of the same through biological barriers will be enhanced.